xanthohumol and Obesity

Two hydrogenated xanthohumol (XN) derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation.. To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance-specifically Bacteroidetes and Tenericutes-alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host.. Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.

Topics: Adipose Tissue, White; Animals; Bile Acids and Salts; Diet, High-Fat; Feces; Flavonoids; Gastrointestinal Microbiome; Gene Expression Regulation; Male; Metabolic Syndrome; Mice, Inbred C57BL; Obesity; Panniculitis; Propiophenones; RNA, Ribosomal, 16S

Xanthohumol (XN), a prenylated chalcone from hops, has been reported to exhibit a variety of health-beneficial effects. However, poor bioavailability may limit its application in the prevention and therapy of diseases. The objective of this study was to determine whether a micellar solubilization of xanthohumol could enhance the bioavailability and biological efficacy of xanthohumol in a Western-type diet (WTD) induced model of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). After 3 weeks feeding with WTD, XN was additionally applied per oral gavage as micellar solubilizate (s-XN) or native extract (n-XN) at a daily dose of 2.5 mg/kg body weight for a further 8 weeks. Control mice received vehicle only in addition to the WTD. WTD-induced body weight-gain and glucose intolerance were significantly inhibited by s-XN application. Furthermore, WTD-induced hepatic steatosis, pro-inflammatory gene expression (MCP-1 and CXCL1) and immune cell infiltration as well as activation of hepatic stellate cells (HSC) and expression of collagen alpha I were significantly reduced in the livers of s-XN-treated mice compared to WTD controls. In contrast, application of n-XN had no or only slight effects on the WTD-induced pathological effects. In line with this, plasma XN concentration ranged between 100-330 nmol/L in the s-XN group while XN was not detectable in the serum samples of n-XN-treated mice. In conclusion, micellar solubilization enhanced the bioavailability and beneficial effects of xanthohumol on different components of the metabolic syndrome including all pathological steps of NAFLD. Notably, this was achieved in a dose more than 10-fold lower than effective beneficial doses of native xanthohumol reported in previous in vivo studies.

Topics: Animals; Biological Availability; Chemokine CCL2; Chemokine CXCL1; Diabetes Mellitus; Diet, Western; Disease Models, Animal; Flavonoids; Hepatic Stellate Cells; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Micelles; Non-alcoholic Fatty Liver Disease; Obesity; Propiophenones

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and β, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.

Topics: Animals; Cell Line; Cognitive Dysfunction; Diet, High-Fat; Disease Models, Animal; Flavanones; Flavonoids; Humans; Liver; Male; MCF-7 Cells; Metabolic Syndrome; Mice; Muscles; Obesity; Plasma; Propiophenones; Spatial Learning; Spatial Memory

We previously showed that xanthohumol-rich hop extract (XRHE, ~18% xanthohumol) exerts anti-obesity effects in rats fed a high-fat diet through regulation of fatty acid metabolism. In this study, we examined the effects of dietary purified xanthohumol from XRHE (PX, ~91.9% xanthohumol) in KK-Ay mice in order to understand the anti-obesity effects of xanthohumol alone because XRHE contains 82% unknown compounds. Dietary consumption of PX significantly inhibited an increase in the visceral fat weight of mice compared to those fed control diet without PX. Plasma leptin level was significantly lower in the PX-fed group than in the control group. Dietary PX lowered hepatic fatty acid synthesis by down-regulation of SREBP1c mRNA expression in the liver. On the other hand, fatty acid β-oxidation in the liver was promoted by dietary PX through the up-regulation of PPARα mRNA expression. Moreover, the fecal levels of fatty acids and carbohydrates increased by dietary PX. PX inhibited lipase or α-amylase activity in vitro. Thus, we found that PX may exert anti-obesity effects through the regulation of lipid metabolism and inhibition of intestinal fat and carbohydrate absorption, and that xanthohumol alone may exert anti-obesity effects.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus; Disease Models, Animal; Fasting; Fatty Acids; Flavonoids; Humulus; Intestinal Mucosa; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred Strains; Obesity; Plant Extracts; Propiophenones; Sterol Regulatory Element Binding Protein 1

Xanthohumol (XN) is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The dose-dependent effects of XN on glucose and lipid metabolism in a preclinical model of metabolic syndrome were the focus of our study. Forty-eight male C57BL/6J mice, 9 weeks of age, were randomly divided into three XN dose groups of 16 animals. The mice were fed a high-fat diet (60% kcal as fat) supplemented with XN at dose levels of 0, 30, or 60 mg/kg body weight/day, for 12 weeks. Dietary XN caused a dose-dependent decrease in body weight gain. Plasma levels of glucose, total triglycerides, total cholesterol, and MCP-1 were significantly decreased in mice on the 60 mg/kg/day treatment regimen. Treatment with XN at 60 mg/kg/day resulted in reduced plasma LDL-cholesterol (LDL-C), IL-6, insulin and leptin levels by 80%, 78%, 42%, and 41%, respectively, compared to the vehicle control group. Proprotein Convertase Subtilisin Kexin 9 (PCSK-9) levels were 44% lower in the 60 mg/kg dose group compared to the vehicle control group (p ≤ 0.05) which may account for the LDL-C lowering activity of XN. Our results show that oral administration of XN improves markers of systemic inflammation and metabolic syndrome in diet-induced obese C57BL/6J mice.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Cholesterol, LDL; Dietary Fats; Flavonoids; Humulus; Insulin; Interleukin-6; Leptin; Lipid Metabolism; Liver; Male; Mice; Obesity; Propiophenones; Proprotein Convertase 9

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that stimulate the expression of genes involved in fatty acid and cholesterol biosynthesis. Here, we demonstrate that a prenylated flavonoid in hops, xanthohumol (XN), is a novel SREBP inactivator that reduces the de novo synthesis of fatty acid and cholesterol. XN independently suppressed the maturation of SREBPs of insulin-induced genes in a manner different from sterols. Our results suggest that XN impairs the endoplasmic reticulum-to-Golgi translocation of the SREBP cleavage-activating protein (SCAP)-SREBP complex by binding to Sec23/24 and blocking SCAP/SREBP incorporation into common coated protein II vesicles. Furthermore, in diet-induced obese mice, dietary XN suppressed SREBP-1 target gene expression in the liver accompanied by a reduction of the mature form of hepatic SREBP-1, and it inhibited the development of obesity and hepatic steatosis. Altogether, our data suggest that XN attenuates the function of SREBP-1 by repressing its maturation and that it has the potential of becoming a nutraceutical food or pharmacological agent for improving metabolic syndrome.

Topics: Animals; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Diet; Fatty Liver; Flavonoids; Humans; Mice; Mice, Inbred C57BL; Obesity; Propiophenones; Sterol Regulatory Element Binding Protein 1

Xanthohumol is the major prenylated flavonoid of female inflorescences of the hop plant (Humulus lupulus L.) and is a hydrophobic flavonoid. We examined the effects of dietary xanthohumol-rich hop extract in obese rats that was induced by feeding a high-fat diet. Dietary xanthohumol-rich hop extract significantly lowered the body weight gain of these rats compared to rats fed a high-fat diet without the extract. The increase of body weight, liver weight, and triacylglycerol levels in the plasma and liver of the rats fed a high-fat diet was ameliorated by dietary xanthohumol-rich hop extract. Dietary xanthohumol-rich hop extract tended to reduce hepatic fatty acid synthesis through the reduction of hepatic SREBP1c mRNA expression in the rats fed a high-fat diet. The excreted of triacylglycerol into feces also was promoted by dietary xanthohumol-rich hop extract. Plasma adiponectin levels in the rats fed a high-fat diet also tended to be elevated by dietary xanthohumol-rich hop extract. Thus, xanthohumol-rich hop extract may inhibit the increase of body weight, liver weight, and triacylglycerol in the plasma and liver induced by feeding high-fat diet through the regulation of hepatic fatty acid metabolism and inhibition of intestinal fat absorption. Therefore, xanthohumol-rich hop extract may exert preventive function on the increase of body weight and tissue triacylglycerol levels by overnutrition.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Diet, High-Fat; Dietary Fats; Fatty Acids; Feces; Flavonoids; Gene Expression; Humulus; Intestinal Absorption; Liver; Male; Obesity; Organ Size; Plant Extracts; Propiophenones; Rats; Rats, Wistar; RNA, Messenger; Sterol Regulatory Element Binding Protein 2; Triglycerides; Weight Gain

Obesity contributes to increased risk for several chronic diseases including cardiovascular disease and type 2 diabetes. Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus), was tested for efficacy on biomarkers of metabolic syndrome in 4 week old Zucker fa/fa rats, a rodent model of obesity. Rats received daily oral doses of xanthohumol at 0, 1.86, 5.64, and 16.9 mg/kg BW for 6 weeks. All rats were maintained on a high fat (60% kcal) AIN-93G diet for 3 weeks to induce severe obesity followed by a normal AIN-93G (15% kcal fat) diet for the last 3 weeks of the study. Weekly food intake and body weight were recorded. Plasma cholesterol, glucose, insulin, triglyceride, and monocyte chemoattractant protein-1 (MCP-1) levels were assessed using commercial assay kits. Plasma and liver tissue levels of XN and its metabolites were determined by liquid-chromatography tandem mass spectrometry. Plasma and liver tissue levels of xanthohumol were similar between low and medium dose groups and significantly (p<0.05) elevated in the highest dose group. There was a dose-dependent effect on body weight and plasma glucose levels. The highest dose group (n=6) had significantly lower plasma glucose levels compared to the control group (n=6) in male but not female rats. There was also a significant decrease in body weight for male rats in the highest dose group (16.9 mg/kg BW) compared to rats that received no xanthohumol, which was also not seen for female rats. Plasma cholesterol, insulin, triglycerides, and MCP-1 as well as food intake were not affected by treatment. The findings suggest that xanthohumol has beneficial effects on markers of metabolic syndrome.

Topics: Animals; Blood Glucose; Dose-Response Relationship, Drug; Eating; Fasting; Female; Flavonoids; Male; Molecular Structure; Obesity; Propiophenones; Rats; Rats, Zucker; Weight Loss

A novel series of benzimidazole derivatives was prepared and evaluated for their diacylglycerol acyltransferase (DGAT) inhibitory activity using microsome from rat liver. Among the newly synthesized compounds, furfurylamine containing benzimidazole carboxamide 10j showed the most potent DGAT inhibitory effect (IC(50)=4.4 μM) and inhibited triglyceride formation in HepG2 cells. Furthermore, compound 10j reduced body weight gain of Institute of Cancer Research mice on a high-fat diet and decreased levels of total triglyceride, total cholesterol, and LDL-cholesterol in the blood accompanied with a significant increase in HDL-cholesterol level.

Topics: Animals; Benzimidazoles; Diacylglycerol O-Acyltransferase; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Hep G2 Cells; Humans; Mice; Mice, Obese; Microsomes, Liver; Molecular Structure; Obesity; Rats; Structure-Activity Relationship; Triglycerides

Xanthohumol (XN) and guggulsterone (GS) have each been shown to inhibit adipogenesis and induce apoptosis in adipocytes. In the present study effects of the combination of XN + GS on 3T3-L1 adipocyte apoptosis and adipogenesis were investigated. Mature adipocytes were treated with XN and GS individually and in combination. XN and GS individually decreased cell viability, but XN + GS caused an enhanced decrease in viability and potentiated induction of apoptosis. Likewise, XN + GS caused a potentiated increase in caspase-3/7 activation, whereas neither of the compounds showed any effect individually. In addition, western blot analysis revealed that XN + GS increased Bax expression and decreased Bcl-2 expression, whereas individual compounds did not show any significant effect. XN and GS both decreased lipid accumulation. Individually, XN at 1.5 microM and GS at 3.12 microM decreased lipid accumulation by 26 +/- 4.5% (P < .001) each, whereas XN1.5 + GS3.12 decreased lipid accumulation by 78.2 +/- 1.8% (P < .001). Moreover, expression of the adipocyte-specific proteins was down-regulated with XN1.5 + GS3.12, but no effect was observed with the individual compounds. Finally, XN + GS caused an enhanced stimulation of lipolysis. Thus, combination of XN and GS is more potent in exerting anti-obesity effects than additive effects of the individual compounds.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Anti-Obesity Agents; Apoptosis; bcl-2-Associated X Protein; Caspases; Cell Survival; Commiphora; Down-Regulation; Drug Therapy, Combination; Flavonoids; Gene Expression; Lipid Metabolism; Lipolysis; Mice; Obesity; Phytotherapy; Plant Extracts; Pregnenediones; Propiophenones; Proto-Oncogene Proteins c-bcl-2